The main GOAL of this proposal is to test the hypothesis that, based on the differences in permeability and lipophilicity of the cornea and the conjunctiva, strategies can be developed to minimize systemic absorption while simultaneously promoting the ocular absorption of topical ocular drugs. Beta blockers have been chosen for study because of their growing importance as anti-glaucoma drugs and because of a pressing need to reduce their incidence of systemic side effects. There are four SPECIFIC AIMS in this research: (1) To confirm our preliminary findings that, beyond a certain drug lipophilicity, the conjunctiva favors the absorption of water-soluble drugs while the cornea favors the absorption of oil-soluble drugs; thus, a range of drug lipophilcity can be defined within which a drug vehicle is most effective in minimizing the ratio of systemic to ocular drug absorption, (2) To demonstrate that the relative contribution of the conjunctival and the nasal mucosae to the systemic absorption of topical beta blockers, hence systemic drug bioavailability, is a function of drug properties and composition of the drug vehicle, (3) To evaluate the influence of existing drug vehicles on the balance between ocular and systemic drug absorption; these include aqueous solutions, polymer solutions, ointments, and gels, and (4) To demonstrate that an erodible polymeric insert is more effective than existing vehicles in minimizing the ratio of systemic to ocular absorption following both single and multiple doses. These experiments will be performed in live rabbits as well as isolated conjunctivas and corneas from eyebank and pigmented rabbit eyes. The principal METHODOLOGY includes (1) the use of lucite-block perfusion chambers to evaluate conjunctival and corneal drug absorption in vitro, and (2) the sampling of plasma and anterior segment tissues at various times following topical ocular drug application for determination of systemic and ocular drug bioavailability. HPLC and radioreceptor assays will be the analytical methodology. The IMPORTANCE of this research is that it establishes systemic absorption as an equally important factors as ocular absorption in the design, selection, and regulatory approval of new ophthalmic drugs, vehicles, and formulations for topical ocular administration. Moreover, it lays the foundation for subsequent clinical and laboratory studies to expose other differences between the cornea and the conjunctiva that can also be used to target topically applied drugs into the eye and away from the blood, thereby reducing systemic side effects and improving drug safety and efficacy.